Asymmetric catalysis is the most efficient method for generating products with high enantiomeric purity, as the asymmetry of the catalyst is multiplied many times over in generating the chiral product. These chiral products have found numerous applications as building blocks for single enantiomer pharmaceuticals as well as in some agrochemicals. The asymmetric catalysts employed can be enzymatic or synthetic in nature. The latter types of catalyst have much greater promise than the former due to much greater latitude of applicable reaction types. Synthetic asymmetric catalysts are usually composed of a metal reaction center surrounded by one or more organic ligands. The ligands usually are generated in high enantiomeric purity, and are the agents inducing the asymmetry. These ligands are in general difficult to make and therefore expensive. A notable exception are chiral phosphine-aminophosphine ligands useful as metal complexes for asymmetric catalysis which are readily prepared and air-stable, and have been described by Boaz et al. in U.S. Pat. No. 6,590,115.
The asymmetric hydrogenation of β-ketoesters to β-hydroxyesters has received significant attention, particularly as these products have a number of industrial applications, not the least of which is a synthetic intermediate in the synthesis of atorvastatin. The complexes that are used for this type of hydrogenation are largely ruthenium-based, with the most effective catalysts derived from axially chiral ligands such as BINAP. See, for example, Mashima et al. J. Org. Chem. 1994, 59, 3064–3076; and Kitamura, et al., Org. Synth. 1992, 71, 1–13. There are a number of methods to prepare ruthenium complexes of bidentate chiral ligands. These methods, many of which are multi-step, are often troublesome and not particularly general, resulting in complexes with varying hydrogenation activities and enantioselectivities. Perhaps the most versatile, general, and useful ruthenium complexes have methallyl ancillary ligands in addition to the chiral bis-phosphine. See, for example, Genet et al., Tetrahedron:Asymm. 1991, 2, 43–46; Genet et al., Tetrahedron:Asymm. 1994, 5, 665–674; and Genet et al., Tetrahedron:Asymm. 1994, 5, 675–690. These methallyl species are generally prepared using multistep processes with harsh reaction conditions (e.g., strong acid), which may not be compatible with phosphine-aminophosphine ligands. One of the simplest preparations of ruthenium complexes is by ligand displacement from commercially available species such as tris(triphenylphosphine)ruthenium dichloride. These preparations have generally involved the reaction of chiral bidentate bis-phosphine ligands with the latter complex and result in ruthenium dichloride complexes containing one chiral bidentate ligand and one (achiral) triphenylphosphine (Mezzetti, A.; Consiglio, G. J. Chem. Soc., Chem. Commun. 1991, 1675–1677.). There have been relatively few complexes prepared using this methodology, and although certain species show high enantioselectivity for 1,3-diketone hydrogenations, the hydrogenation of β-ketoester substrates has proceeded with only moderate enantioselectivity (Mezzetti, A.; Tschumper, A.; Consiglio, G. J. Chem. Soc. Dalton Trans. 1995, 49–56; Stoop, R. M.; Mezzetti, A.; Spindler, F. Organometallics 1998, 17, 668–675; Maienza, F.; Santoro, F.; Spindler, F.; Malan, C.; Mezzetti, A. Tetrahedron:Asymm. 2002, 13, 1817–1824.). In no cases have ruthenium complexes of phosphine-aminophosphines been prepared in this manner.